While still teenagers, they formed in 2000 after guitarist Cole Alexander and bassist Jared Swilley left the Renegades, and guitarist Ben Eberbaugh left the Reruns. Drummer Joe Bradley joined a few months later. They released their first 7" in late 2001/early 2002 on their own Die Slaughterhauslabel.

Just days before a tour was to begin in December 2002, Ben Eberbaugh was driving a car that was struck by a drunk driver going the wrong way on a highway. He was killed but the band carried on, believing that Eberbaugh would want them to continue. The band´s debut full length album, Black Lips! was released on Bomp! Records in 2003. Eberbaugh was replaced by Jack Hines, a friend of the band members, and they recorded their second studio album, We Did Not Know The Forest Spirit Made The Flowers Grow, with him. Hines too was eventually replaced by current guitarist, and former Renegades member, Ian Saint Pé, in 2004.

The Black Lips have a reputation for crazy live shows that have included vomiting, urinating, nudity, band members kissing, fireworks, and a chicken. The frequency of the group´s outrageous stage antics has declined, as they claim to have matured "a little bit". They have slowly built a fanbase that appreciates their energy and style that is a rough mishmash of blues, rock, doo-wop, country, and punk. They gained national attention in 2006 with features in Spin and Rolling Stone magazines. The band got exposure in the New York Times for being the hardest working band during the 2007 South by Southwest music festival in Austin, Texas, in which they played a dozen shows over a three-day period.

Their debut for Vice Records, Los Valientes Del Mundo Nuevo, was released in February 2007. It is supposed to have been recorded at a bar in Tijuana, Mexico, but fans, musicians, and journalists have speculated that some or most of it was recorded in a studio with John Reis. The band has denied these claims, but critics cite noticeable differences in reverb and tape and crowd noise.

In September 2007 their most recent album entitled Good Bad Not Evil was released. The Black Lips made their American national television debut in October 2007 on Late Night with Conan O´Brien and played "O Katrina". In 2008, Boston newspaper The Phoenix named them the Best New Band from Georgia.